Despite enormous research efforts during the last decades and advanced cancer treatments, cancer remains a major public health problem worldwide and is the second leading cause of death in the United States. In the US population, incidence and death rates are even increasing for several cancer types, including liver and pancreas—two of the most fatal cancers (Siegel et al. 2016). Thus, there is still an urgent need to obtain additional and improved treatment options for fighting cancer besides the established chemotherapies, radiation and upcoming immunotherapies.
Interfering with the cancer metabolism is another principle to tackle tumor growth. In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate energy, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect” (Vander Heiden et al. 2009). Aerobic glycolysis in the cytoplasm leads to pyruvate generated from glucose, which is not transported into mitochondria for total oxidation for yielding more energy but is converted to lactate, originally described by Warburg (Hsu et al. 2008). Lactate is transferred to the liver, where the carbon skeleton is used to synthesize glucose known as the “neoplastic or pathological Cori cycle” contributing to the clinical metabolic state of Cachexia, a condition existing in neoplastic patients who suffer massive loss of normal body mass as the neoplasm continues its growth (Tisdale 2002). Consequently, inhibiting aerobic glycolysis (Warburg effect) and/or neoplastic anabolism (pathological Cori cycle) may be another effective way to interfere with cancer metabolism and effectively treat cancer patients. The inhibition of glycolysis in connection with the Warburg effect for cancer treatment has been described by Pelicano, H. et al. (2006) and Scatena et al. (2008).
However, the relevance of mitochondrial respiration in tumors is varied depending on tumor type. An oxidative class of tumors and tumors with dual capacity for glycolytic and oxidative metabolism is evident and the importance of mitochondria in tumor cell survival and proliferation, including utilization of alternative oxidizable substrates such as glutamine and fatty acids, has been increasingly appreciated. The diversity of carbon substrate utilization pathways in tumors is indicative of metabolic heterogeneity that may not only be relevant across different types of cancer but also manifest within a group of tumors that otherwise share a common diagnosis (Caro et al. 2012). Accordingly, tumors show heterogeneity in fuel utilization even within the same disease entity with some having a significant mitochondrial component, marked by elevated oxidative phosphorylation (OXPHOS), increased contribution of mitochondria to total cellular energy budget, greater incorporation of fatty acid- and glucose-derived carbons into the TCA cycle, and increased lipogenesis from these carbon substrates (Caro et al. 2012).
Indeed, recent evidence supports the hypothesis that acquired resistance to therapy is accompanied by a metabolic shift from aerobic glycolysis toward respiratory metabolism, suggesting that metabolic plasticity can have a role in survival of cells responsible for tumor relapse, suggesting that metabolic plasticity can have a role in survival of cells responsible for tumor relapse. For example, it has been observed that several drug-resistant tumor cells show a higher respiratory activity than parental cells. The metabolic adaptation allows OXPHOS-addicted cancer cells to easily survive drug treatments, but leaves cells susceptible to inhibitors of OXPHOS (Denise et al. 2015).
Cancer cell mitochondria are structurally and functionally different from their normal counterparts. Moreover, tumor cells exhibit an extensive metabolic reprogramming that renders them more susceptible to mitochondrial perturbations than non-immortalized cells. Based on these premises, mitochondrially-targeted agents emerge as a means to selectively target tumors. The correction of cancer-associated mitochondrial dysfunctions and the (re)activation of cell death programs by pharmacological agents that induce or facilitate mitochondrial membrane permeabilization represent attractive strategies for cancer therapy. Further, autophagy in the tumor stroma and oxidative mitochondrial metabolism (OXPHOS) in cancer cells can both dramatically promote tumor growth, independently of tumor angiogenesis (Salem et al. 2012) and that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, “energy transfer” or “metabolic-coupling” between the tumor stroma and epithelial cancer cells “fuels” tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells, the “reverse Warburg effect” (Whitaker-Menezes et al. 2011).
Accordingly, these findings provide a rationale and for novel strategies for anti-cancer therapies by employing inhibitors of OXPHOS and mitochondrial functions. Mitochondrial targeted anti-cancer drugs are reviewed by Fulda et al. (2010) and Weinberg and Chandel (2015) including inhibitors of mitochondrial complex 1, inhibitors of the electron transfer chain (ETC) complex, inhibitors of mitochondrial ribosomal machinery, inhibitors of the translation of ETC subunits, inhibitors of mitochondrial chaperone proteins, inhibitors of glutaminases, aminotransferases or glutamate dehydrogenases, short term inhibition of autophagy, mitochondrial-targeted antioxidants.
WO 2008/054475 A2 describes coumarin derivatives as inhibitors of neuraminidase for use in reducing or inhibiting biofilm formation for non-medical use.
Recently, mitochondrial RNA polymerase (POLRMT, also known as h-mtRNAP) has been proposed as a new target in acute myeloid leukemia (Bralha et al. 2015). POLRMT is responsible for the transcription of the 13 subunits of the OXPHOS complexes, two rRNAs and 22 tRNAs required for mitochondrial translation and acts as the RNA primase for mitochondrial DNA replication (Scarpulla 2008, Wanrooij et al. 2010). Therefore, this enzyme is of fundamental importance for both expression and replication of the human mitochondrial genome (Amold et al. 2012).
A number of nucleoside analogues used as antiviral agents to target viral RNA polymerases demonstrate off-target inhibition of POLRMT (Arnold et al. 2012); POLRMT is distantly related to bacteriophage T7 class of single-subunit RNAPs. The finding that treatment with 2-C-methyladenosine, identified as an inhibitor of the RNA-dependent RNA polymerase of hepatitis C virus (Carroll et al. 2003), triggers the death of AML cells allegedly through rather unspecific inhibition of mitochondrial transcription confirms this rational (Bralha et al. 2015).
Thus, there is a need for alternative novel compounds, which specifically inhibit POLRMT and are suitable for use as a medicament. In particular, a need exists for novel compounds that can be used in the treatment of cancer, preferably melanoma, metastatic melanoma, pancreatic cancer, hepatocellular carcinoma, lymphoma, acute myeloid leukemia, breast cancer, glioblastoma, cervical cancer, renal cancer, colorectal cancer or ovarian cancer. Furthermore, POLRMT inhibitors are of interest, which can be used in a method for treating cancer in simultaneous, alternating or subsequent combination with another cancer therapy.
Accordingly, the present invention provides specific POLRMT inhibitors for the treatment of cancer.